About 2.2 million deaths in the United States are due to cancer. Current therapies include surgical excision of affected tissue, chemotherapy and immunotherapy. Tolerance is a major hindrance to effective immunotherapy. CD8+ T cells, which are an important adaptive immune cell type responsible for lysing tumor cells and virus-infected cells, become non-functional and unable to eradicate tumor cells. Yet, in some animal models and human patients, the tolerized T cells persist. The objective of this project is to determine the mechanism for persistence of T cells in a tolerizing tumor environment. Using prostate cancer-specific T cells, the following specific aims will be investigated: (1) identify molecules that support survival of tolerized T cells and (2) identify cell types that interact with tolerized T cells. We hypothesize that T cells are maintained in a tolerizing tumor environment by cytokines that are involved in T cell survival, such as interleukin (IL)-15 and IL-7. Also, the mechanism of tolerized 2C T cell persistence may depend on cell-contact mediated processes which should be reflected in the cellular interactions observed in the prostate. Flow cytometry, fluorescence microscopy, and in vitro culture assay techniques will be used to achieve these aims. Novel molecules that may support T cell survival will also be identified by screening prostate tissue homogenates of our tumor model with a multiplex cytokine assay system. Results from this project will provide a mechanistic basis for developing more effective strategies to break tolerance while maintaining antigen-specific T cells in the tumor environment. In addition, these results would provide novel approaches for treating chronic infections that also have functionally impaired but persistent T cells, and provide ways to limit T cell survival leading to graft rejection. RELEVANCE TO PUBLIC HEALTH: Cancer is a disease that affects millions of people worldwide and will account for at least 2.2 million of the deaths in the U.S. this year (2007). T cells are cells that mature in the thymus, an organ in the neck region, which are responsible for eliminating cancerous cells. This project aims to understand how to enhance the survival and function of these T cells that fight cancer.